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Stegeman H, Span PN, Rijken PF, et al. Dasatinib Inhibits DNA Repair after Radiotherapy Specifically in pSFK-Expressing Tumor Areas in Head and Neck Xenograft Tumors. Transl Oncol. 2013;6(4):413-9doi: 10.1593/tlo.13259.
Stegeman, H., Span, P. N., Rijken, P. F., Cockx, S. C., Wheeler, D. L., Iida, M., van der Kogel, A. J., Kaanders, J. H., & Bussink, J. (2013). Dasatinib Inhibits DNA Repair after Radiotherapy Specifically in pSFK-Expressing Tumor Areas in Head and Neck Xenograft Tumors. Translational oncology, 6(4), 413-9. https://doi.org/10.1593/tlo.13259
Stegeman, Hanneke, et al. "Dasatinib Inhibits DNA Repair after Radiotherapy Specifically in pSFK-Expressing Tumor Areas in Head and Neck Xenograft Tumors." Translational oncology vol. 6,4 (2013): 413-9. doi: https://doi.org/10.1593/tlo.13259
Stegeman H, Span PN, Rijken PF, Cockx SC, Wheeler DL, Iida M, van der Kogel AJ, Kaanders JH, Bussink J. Dasatinib Inhibits DNA Repair after Radiotherapy Specifically in pSFK-Expressing Tumor Areas in Head and Neck Xenograft Tumors. Transl Oncol. 2013 Aug 01;6(4):413-9. doi: 10.1593/tlo.13259. Print 2013 Aug. PMID: 23908684; PMCID: PMC3730016.
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Transl Oncol. 2013 Aug 01;6(4):413-9. doi: 10.1593/tlo.13259. Print 2013 Aug.

Dasatinib Inhibits DNA Repair after Radiotherapy Specifically in pSFK-Expressing Tumor Areas in Head and Neck Xenograft Tumors.

Translational oncology

Hanneke Stegeman, Paul N Span, Paul F J W Rijken, Simone C Cockx, Deric L Wheeler, Mari Iida, Albert J van der Kogel, Johannes H A M Kaanders, Johan Bussink

Affiliations

  1. Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

PMID: 23908684 PMCID: PMC3730016 DOI: 10.1593/tlo.13259

Abstract

Src family kinases (SFKs) have been implicated in resistance to both radiation and epidermal growth factor receptor (EGFR) inhibition. Therefore, we investigated whether inhibition of SFK through dasatinib (DSB) can enhance the effect of radiotherapy in two in vivo human head and neck squamous cell carcinoma (HNSCC) models. Response to DSB and/or radiotherapy was assessed with tumor growth delay assays in two HNSCC xenograft models, SCCNij153 and SCCNij202. Effects on EGFR signaling were evaluated with Western blot analysis, and effects on DNA repair, hypoxia, and proliferation were investigated with immunohistochemistry. DSB and radiotherapy induced a significant growth delay in both HNSCC xenograft models, although to a lesser extent in SCCNij202. DSB did not inhibit phosphorylated protein kinase B (pAKT) or phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) but did inhibit (phosphorylated) DNA-dependent protein kinase. Moreover, DSB reduced repair of radiation-induced DNA double-strand breaks as shown by an increase of p53-binding protein 1 (53BP1) staining 24 hours after radiation. This effect on DNA repair was only observed in the cell compartment where phosphorylated SFK (pSFK) was expressed: for SCCNij153 tumors in both normoxic and hypoxic areas and for SCCNij202 tumors only in hypoxic areas. No consistent effects of DSB on hypoxia or proliferation were observed. In conclusion, DSB enhances the effect of radiotherapy in vivo by inhibition of radiation-induced DNA repair and is a promising way to improve outcome in HNSCC patients.

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